The invention is in the field of drug delivery. Specifically, the invention is directed to a drug delivery system that provides enterally-administered pharmaceuticals in a two pulse fashion.
The ability to deliver a drug in a manner that targets the drug for absorption at a specific region of the gastrointestinal tract is desirable for many reasons. Such a delivery system would allow the medical practitioner to locally treat gastrointestinal diseases. Local treatment of gastrointestinal diseases would avoid systemic side effects of drugs or inconvenient and painful direct delivery of drugs. In addition, such a delivery system could potentially increase the efficiency of a drug, thus allowing a reduction of the minimum effective dose of the drug. A delivery system that could target a drug to a specific region of the gastrointestinal tract would thus be useful for the treatment of a wide variety of diseases and conditions.
WO 97/25979 describes a drug-delivery device for the targeting of various parts of the gastrointestinal tract. A core containing a drug is coated with a hydrophobic polymer which contains hydrophilic, non-water-soluble particles embedded therein. These particles serve as channels for aqueous medium entering the core and for the release of drugs by diffusion through these channels. This delivery system can target various parts of the gastrointestinal tract and slowly release its drug load.
U.S. Pat. No. 5,525,634 describes a delivery device that contains a drug in combination with a matrix. The matrix contains a saccharide-containing polymer. The matrix-drug combination can be coated or uncoated. The polymer is resistant to chemical and enzymatic degradation in the stomach and susceptible to enzymatic degradation in the colon by colonic bacteria.
EP 485,840 (Rxc3x6hm GmbH), discloses a gastrointestinal delivery device containing, as a coating, a mixture of a polysaccharide and Eudragit(copyright)(trademark). However, this formulation does not allow control of the rate of liquid entry into the formulation. Therefore, control of the site of release of the drug cannot be achieved. Further, the polysaccharide is not provided in particulate form.
U.S. Pat. No. 4,627,850 (Deters et al.) discloses an osmotic capsule for the controlled rate delivery of a drug comprising outer and inner walls each formed of a different polymeric material, the inner wall defining a space containing the drug, with a passageway through the walls connecting the exterior of the outer wall with the interior of the inner wall.
U.S. Pat. No. 4,904,474 (Theuwes et al.) discloses a colonic drug delivery device comprising means for delaying the delivery in the drug and in the small intestine and means for delivering the drug in the colon. This device comprises osmotic means for forcing the active pharmaceutical agent out from the compartment in which it is contained through an exit provided in said compartment, into the colon. The means for delaying delivery in the stomach or in the small intestine are pH-resistant coatings. The delay in delivery of the drug is time-based.
U.S. Pat. No. 5,593,697 describes a pharmaceutical implant containing a biologically active material, an excipient comprised of at least one water soluble material and at least one water insoluble material, and a polymer film coating adapted to rupture at a predetermined period of time after implantation.
U.S. Pat. No. 4,252,786 describes a controlled release tablet for the administration of medicinal agents over a prolonged period of time.
U.S. Pat. Nos. 5,260,069 and 5,472,708 describe a dosage form for delivering drugs, and particularly drugs that cannot be released by diffusion through a porous coating, such as water insoluble drugs.
U.S. Pat. No. 4,897,270 describes a pharmaceutical tablet comprising a tablet core and a film coat to mask the taste of the core. The core disintegrates immediately following rupture of the film coat.
U.S. Pat. No. 5,204,121 describes a drug release system in pellet form where the pellets consist of a core containing the active compound. The core is surrounded by a polymer-containing jacket and a undigestible lacquer layer that is permeable to water. The outer lacquer layer does not dissolve but is said to carry water to the migration controlling jacket layer which then brings the liquid in contact with the drug containing core.
U.S. Pat. No. 4,891,223 describes compositions for the sustained release of a pharmaceutical, comprising a drug-containing core, a first coating containing a polymer swellable upon penetration of the surrounding media, and a second coating, enveloping the first coating, comprising a polymer that is water-soluble and that forms a semi-permeable barrier. The outer coating is said to permit diffusion of the media, into the first coating and then diffusion of the dissolved drug into the surrounding media. The second coating must have requisite stretchability to prevent rupture of a second coating due the swelling of the first coating until a specific time in the release pattern.
U.S. Pat. No. 4,327,725 describes a variation of a basic osmotic device for drug release. The structure of the device is an active agent enclosed in a hydrogel layer that is enclosed in a semi-permeable membrane. The semi-permeable membrane allows diffusion of external fluid but does not allow diffusion of the solution of active agent to the surrounding environment. The hydrogel swells with absorption of external fluid and exerts pressure on the solution of active agent in the external fluid. The solution of the active agent in the external fluid is then delivered to the surrounding media through a single specially constructed passageway through the hydrogel layer and the membrane.
Some pulsatile delivery systems exist in the art. U.S. Pat. No. 5,162,117 describes a two pulse tablet of flutamide for the treatment of prostate cancer. The first pulse is contained in an immediate release layer while the second pulse is obtained from a core which contains a solid dispersion of the flutamide in a carrier. The pulses are separated by a film layer of an enteric coating at 4-15% weight percent of the core. The enteric coating slowly dissolves after the delivery of the first pulse of drug allowing the release of the second pulse. Enteric coatings as a delaying layer suffer from disadvantages of lack of parameters to control the precise timing of the delivery of the second pulse and are limited to delivering the second pulse to the small intestine. The slightly acidic environment of the human colon can cause the enteric coating to stop dissolving upon colon entry and may cause the second dose to be undelivered if the delay time between the pulses is longer than the time of transit through the small intestine. This disadvantage would be magnified if the first dose were to be limited to delivery to the small intestine and not to the stomach in which case the delay to the second pulse would be limited to about 3-4 hours.
U.S. Pat. No. 5,260,069 describes a capsule which contains a plurality of pellets with varying delay times to drug release. By mixing pellets of different delay times one can obtain pulsatile delivery of the drug. The delay time to drug delivery of the pellets is controlled by the pellets containing a swelling agent and the drug and being surrounded by a membrane that contains a water insoluble film and a water soluble film. The water soluble component of the film dissolves slowly thereby weakening the membrane. Water entry into the pellets causes them to swell and burst the weakened membrane. U.S. Pat. No. 5,260,068 describes a unit dosage form that contains populations of pellets or particles that have different delay times to drug delivery. The drug is contained in the pellet along with an osmotic agent. The pellets are coated with a water permeable, water-insoluble film that allows water diffusion into the pellet. The osmotic agent dissolves in the water causing the pellet to swell and eventually burst to release drug. Differences in the water permeability of the film coating afford the differences in delay time.
These systems suffer from the disadvantage of not being able to control the water entry into the system, and not having a variable parameter that can provide such control. These systems suffer from a further disadvantage in that the pellets naturally spread as they travel through the GI tract. This makes the delivery of the dose less site specific and therefore less efficacious.
WO 98/51287 describes a pulsatile system based on multiple particles in a dosage form. The drug release from the particle is controlled by combinations of controlled release layers, swelling layers and coating layers. The controlled release layer is a slightly crosslinked poly(acrylic acid) polymer of high molecular weight admixed with a water soluble polymer. This system too suffers from the disadvantage of not having many parameters for tailoring the rate of water entry into the pellets. The system suffers from a further disadvantage of the natural spread of the pellets as they travel through the GI tract making the delivery of the dose less site specific and therefore less efficacious.
Lippold, B. C. and Moekel, J. E. (Acta Pharm. Technol. 36(2):97-98 (1990)) describe a two pulse tablet system consisting of a triple laminate of hydroxypropylmethylcellulose (HPMC) prepared by successive direct compressions. The drug was contained in the inner core and the outer layer with a drug free layer separating the two drug containing layers. The thickness of the drug free layer controlled the time between doses within the range of 2.5 to 6.5 hours. This system is based on erosion of the spacer layer and offers less control over time of drug delivery than other systems, Furthermore, the lag time attainable is limited.
Ishino R. et. al. (Chem. Pharm. Bull. 40(11):3036-3041 (1992)) describe a single pulse tablet based on the dry pressing of a partially water permeable layer onto a swellable core which contains drug. The outer shell consisted of hydrogenated castor oil and polyethylene glycol 6000 and could control lag time by changing the thickness or the relative composition of the pressed outer layer.
Conte, U. et. al., (Eur. J. Pharm. Biopharm., 38(6):209-212 (1992)) describe a two pulse tablet for ibuprofen which consists of three layers. The inner core which contains drug is overlaid with a gelling barrier of hydroxypropylmethylcellulose which is drug free. The outer layer contains a drug. Different molecular weights and/or viscosities of the HPMC control the rate of penetration of water through the gelling layer and the rate of erosion of the gelling layer thereby controlling the lag time between pulses. This system is based on erosion of the spacer layer or permeation of the water through the gel layer and offers less control over time of drug delivery than other systems. Furthermore, the lag time attainable is limited.
Otsuka, M. and Matsuda, Y. (Pharm. Res. 11(3):351-354 (1994)) describe a pulse tablet based on a dry coat. The first pulse is delivered by a dry coated outer layer that is pressed on a disintegrating wax matrix core. The core delivers the second pulse. This system does not offer many parameters for controlling the lag time between pulses.
Munday, D. L. (S. T. P. Pharma Sci. 6(3):182-7 (1996)) describes a matrix tablet capable of a bimodal release pattern. Core tablets containing theophylline are pressed in a matrix containing HPMC, lactose and theophylline. The rates of release from each component can be controlled and a bimodal pattern of release can be obtained. There is no teaching as to separating pulses of the drug delivery by controlled amounts of lag time.
WO 99/18938 describes an immediate release gastrointestinal drug delivery system. This system is composed of a drug-containing core that is surrounded by a hydrophobic polymer material into which hydrophilic particulates are embedded. Upon exposure to the gastrointestinal environment, the insoluble hydrophilic particles swell. As a result of this swelling, channels form that serve as conduits for the controlled entry of liquid into the core. The core then swells or otherwise imparts pressure on the coat. At a predetermined time, the coat bursts and the drug is released from the core.
Thus, there is a need for a drug delivery system that provides more than one pulse of a drug, that would allow strict control over the lag time between pulses of the drug, be controllable within wide ranges of lag times and thereby allow the temporal and spatial separation of doses of the same drug or of two different drugs wherever high concentration of a drug for a relatively short period of time is desired. Such a system could improve patient compliance to a drug regimen or offer opportunities of treatment otherwise not attainable.
Recognizing the problems with current methods for delivering efficacious levels of multiple drugs to specific regions of the gastrointestinal tract, and cognizant of the need for drug delivery systems that facilitate patient compliance, the inventors investigated alternate mechanisms for the administration of desired agents to the gastrointestinal tract. These efforts have culminated with the characterization of a unique double pulse drug delivery system that is not only capable of providing one or more desired agents in a desired temporal and spatial manner to specific areas of the gastrointestinal tract, but is also capable of delivering highly concentrated pulses of such agents.
Thus, in a first embodiment, the invention is directed to a double pulse delivery system or device for targeted delivery to one or more specific locations in the gastrointestinal tract or alimentary canal. The double pulse delivery device contains a core material that is encapsulated by an inner coat, which is, in turn encapsulated by outer coat. A third coat, such as an enteric coat or a coat to mask taste or to ease swallowing, is optionally present. The desired agents are incorporated into the outer coat and core. The agent in the outer coat is released in a burst (i.e. immediate) or in a sustained release fashion, as desired. Release of the agent from the outer coat activates a series of steps that results in a bursting of the core, and, as a result, release of the agent contained therein. The release of the desired agent from the outer coat and the release of the desired agent from the core can be adjusted as desired to achieve a predetermined temporal and spatial release of the agents in the patient""s gastrointestinal tract.
In a further embodiment, the invention is directed to a method of treating a patient in need of the same by administering the double pulse delivery system or device as above to the patient.
In a further embodiment, the invention is directed to a method of preparing a double pulse delivery system.